Chronic wasting disease (CWD), the prion disease in cervids (deer and elk), is widespread in North America. The cervid population is huge (approximately 22 million) and venison consumption very significant in USA. The fast spreading CWD is hard to contain, and it may pose a serious threat to human health if it is transmissible to humans, even at a low rate. This proposal will use transgenic (Tg) mouse models to answer three critical questions pertinent to the potential dangers posed by CWD to humans: Can CWD be transmitted to humans directly (Aim 1)? Can CWD be transmitted to humans after passage through secondary hosts (cattle or sheep) (Aim 2)? Has CWD transmission to humans already occurred (Aim 3)? The ultimate goals are to define the risks of direct and indirect CWD transmission to humans and to establish a surveillance program to monitor for human subjects infected by CWD prions. Research Design: For Aims 1 and 2, humanized and cervidized Tg mice will be intracerebrally (i.e.) inoculated with brain homogenates either from human subjects with sporadic Creutzfeldt-Jakob disease (CJD) or from CWD-affected animals including: Rocky Mountain elk, mule deer, white-tail deer, cattle, and sheep;sheep scrapie will also be inoculated as a control. The inoculated animals will then be monitored and compared for the transmission rate, incubation time, neurological symptoms, accumulation and distribution of PrP-Sc, and the glycoforms and conformational stability of PrP-Sc before and after passage in the Tg mice. Secondary transmissions will be done to examine for asymptomatic carriers of prion infectivity. Oral transmissions will be performed for CWD isolates that demonstrated infectivity in humanized Tg mice after i.e. inoculation. For Aim 3, cervidized Tg mice will be i.e. inoculated with brain homogenates from CJD subjects who had consumed venison from CWD endemic areas as well as from sporadic CJD subjects not exposed to CWD. The prion infectivity liters in the brain homogenates will be determined for all involved CJD subjects, and the same infectivity dose will be used for inoculation. A statistically significant higher transmission efficiency of prions from "CWD-exposed" CJD subjects than that of the sporadic CJD subjects unexposed to CWD will suggest that the "CWD-exposed" subject likely acquired his CJD from CWD.